TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis
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Jesse Gore1,5, Kelly E. Craven1,2, Julie L. Wilson1, Gregory A. Cote1,5,6, Monica Cheng1, Hai V. Nguyen3, Harvey M. Cramer4, Stuart Sherman1,5, Murray Korc1,2,5
1Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
4Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
5The Melvin and Bren Simon Cancer Center, and the Center for Pancreatic Cancer Research, Indianapolis, IN 46202, USA
6Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
Murray Korc, e-mail: firstname.lastname@example.org
Jesse Gore, e-mail: email@example.com
Keywords: Pancreatic cancer, Angiogenesis, TGF-β, STAT3, mouse model
Received: January 24, 2015 Accepted: January 28, 2015 Published: February 25, 2015
Pancreatic ductal adenocarcinomas (PDACs) overexpress pro-angiogenic factors but are not viewed as vascular. Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB. Moreover, patient-derived orthotopic xenografts can exhibit tumor angiogenesis, whereas conditioned media (CM) from KRC-derived pancreatic cancer cells (PCCs) enhance endothelial cell (EC) growth and migration, and activate canonical TGF-β signaling and STAT3. Inhibition of the type I TGF-β receptor with SB505124 does not alter endothelial activation in vitro, but decreases pro-angiogenic gene expression and suppresses angiogenesis in vivo. Conversely, STAT3 silencing or JAK1–2 inhibition with ruxolitinib blocks CM-enhanced EC proliferation. STAT3 disruption also suppresses endothelial HDAC9 and blocks CM-induced HDAC9 expression, whereas HDAC9 re-expression restores CM-enhanced endothelial proliferation. Moreover, ruxolitinib blocks mitogenic EC/PCC cross-talk, and suppresses endothelial p-STAT3 and HDAC9, and PDAC progression and angiogenesis in vivo, while markedly prolonging survival of KRC mice. Thus, targeting JAK1–2 with ruxolitinib blocks a final pathway that is common to multiple pro-angiogenic factors, suppresses EC-mediated PCC proliferation, and may be useful in PDACs with a strong pro-angiogenic signature.
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